Prostate cancer progresses from an initially androgen-dependent state to a state of androgen-independence where it no longer is sensitive to androgen ablation therapy. Our hypothesis is that intracellular signal transduction pathways replace the requirement for androgen either by bypassing the Androgen Receptor or by activating the Androgen Receptor so that it functions with little or no androgen--or a combination of these. For our first Aim, we propose to analyze the pathways by which Ras-dependent kinases and Protein Kinase A alter growth and gene expression in androgen-responsive prostate cancer cells. For our second Aim we propose to move "upstream" by analyzing the regulated phosphorylations of the Androgen Receptor and of proteins which bind to this receptor. I. Protein kinase cascades in the conversion of LNCaP cells to androgen- independence. Growth of prostate cancer cells can be fueled by autocrine and paracrine loops which signal through Ras and/or Protein Kinase A. We will analyze the Ras effector pathways responsible for transforming LNCaP cells to androgen independence and the ways they interact with Protein Kinase A. II. Intracellular signals which regulate the Androgen Receptor. Intracellular regulatory kinases can activate the Androgen Receptor so that it functions transcriptionally in the absence of androgen or is sensitized to low levels of androgen. We will analyze the molecular basis for these effects by examining the regulated phosphorylation of the Androgen Receptor and of its binding partners, and identifying the responsible kinases.